Blockade of CTLA-4 Enhances Host Resistance to the Intracellular Pathogen,<i>Leishmania donovani</i>

Murphy, Marianne; Cotterell, Sara E. J.; Gorak, Patricia M. A.; Engwerda, Christian R.; Kaye, Paul M.

doi:10.4049/jimmunol.161.8.4153

Cited by 121 publications

(2 citation statements)

References 56 publications

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“…LAG3 blockade suppressed Tr1 cell development and improved antiparasitic immunity. The blockade of several coinhibitory receptor molecules has shown therapeutic value in experimental VL, including CTLA-4 and PD-1 (23,24,26,27). However, the therapeutic potential of LAG3 and TIM3 blockade in VL is unknown.…”

Section: Resultsmentioning

confidence: 99%

A molecular signature for IL-10–producing Th1 cells in protozoan parasitic diseases

Edwards,

Engel,

de Labastida Rivera

et al. 2023

JCI Insight

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Control of visceral leishmaniasis (VL) depends on proinflammatory Th1 cells that activate infected tissue macrophages to kill resident intracellular parasites. However, proinflammatory cytokines produced by Th1 cells can damage tissues and require tight regulation. Th1 cell IL-10 production is an important cell–autologous mechanism to prevent such damage. However, IL-10–producing Th1 (type 1 regulatory; Tr1) cells can also delay control of parasites and the generation of immunity following drug treatment or vaccination. To identify molecules to target in order to alter the balance between Th1 and Tr1 cells for improved antiparasitic immunity, we compared the molecular and phenotypic profiles of Th1 and Tr1 cells in experimental VL caused by Leishmania donovani infection of C57BL/6J mice. We also identified a shared Tr1 cell protozoan signature by comparing the transcriptional profiles of Tr1 cells from mice with experimental VL and malaria. We identified LAG3 as an important coinhibitory receptor in patients with VL and experimental VL, and we reveal tissue-specific heterogeneity of coinhibitory receptor expression by Tr1 cells. We also discovered a role for the transcription factor Pbx1 in suppressing CD4 + T cell cytokine production. This work provides insights into the development and function of CD4 + T cells during protozoan parasitic infections and identifies key immunoregulatory molecules.

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Section: Resultsmentioning

confidence: 99%

A molecular signature for IL-10–producing Th1 cells in protozoan parasitic diseases

Edwards,

Engel,

de Labastida Rivera

et al. 2023

JCI Insight

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“…In homologous co-cultures of healthy subjects and patients (post- R. felis infection) a negative regulation by PD1 was not seen, possibly explaining the low degree of pathogenicity that is observed in the clinical evolution of these patients. The result observed in co-cultures of healthy subjects and patients (post- R. typhi infection), could be associated with other molecules such as CTLA-4, as it occurs in infections with Leishmania donovani and Mycobacteria However, studies are required to prove this [ 43 , 44 ]. This preliminary data will allow further studies to determine the role of PD1 in Rickettsia infections.…”

Section: Discussionmentioning

confidence: 99%

Rickettsia Vaccine Candidate pVAX1-OmpB24 Stimulates TCD4+INF-γ+ and TCD8+INF-γ+ Lymphocytes in Autologous Co-Culture of Human Cells

et al. 2023

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Background: In recent years, promising vaccination strategies against rickettsiosis have been described in experimental animal models and human cells. OmpB is considered an immunodominant antigen that is recognized by T and B cells. The aim of this study was to identify TCD4+INF-γ+ and TCD8+INF-γ+ lymphocytes in an autologous system with macrophages transfected with the vaccine candidate pVAX1-OmpB24. Lymphocytes and monocytes from 14 patients with Rickettsia were isolated from whole blood. Monocytes were differentiated into macrophages and transfected with the plasmid pVAX1-OmpB24 pVax1. Isolated lymphocytes were cultured with transfected macrophages. IFN-γ-producing TCD4+ and TCD8+ lymphocyte subpopulations were identified by flow cytometry, as was the percentage of macrophages expressing CD40+, CD80+, HLA-I and HLA-II. Also, we analyzed the exhausted condition of the T lymphocyte subpopulation by PD1 expression. Macrophages transfected with pVAX1-OmpB24 stimulated TCD4+INF-γ+ cells in healthy subjects and patients infected with R. typhi. Macrophages stimulated TCD8+INF-γ+ cells in healthy subjects and patients infected with R. rickettsii and R. felis. Cells from healthy donors stimulated with OmpB-24 showed a higher percentage of TCD4+PD1+. Cells from patients infected with R. rickettsii had a higher percentage of TCD8+PD-1+, and for those infected with R. typhi the larger number of cells corresponded to TCD4+PD1+. Human macrophages transfected with pVAX1-OmpB24 activated TCD4+IFN-γ+ and CD8+IFN-γ+ in patients infected with different Rickettsia species. However, PD1 expression played an important role in the inhibition of T lymphocytes with R. felis.

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Endogenous IL-4 is necessary for effective drug therapy against visceral leishmaniasis

et al. 2000

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It is well established that a fully competent immune response is required for the successful drug treatment of visceral leishmaniasis. However, recent studies have cast some doubt as to which elements of the immune response synergize with chemotherapeutic treatment. The role of the Th2 response and IL‐4 in particular during visceral leishmaniasis awaits clarification. We, therefore, examined the effectiveness of sodium stibogluconate treatment on Leishmania donovani infection in BALB/c wild‐type and IL‐4–/– mice. Parasite burdens in L. donovani‐infected IL‐4+/+ and IL‐4–/–, as we have previously shown for B6/129 mice, were similar, despite an apparent type 1 antibody response in infected IL‐4–/– mice, demonstrated by increased levels of parasite‐specific IgG2a and decreased IgG1. Unexpectedly IL‐4–/– mice responded poorly to sodium stibogluconate treatment with increased parasite burdens in all tissues examined. Furthermore, drug therapy of IL‐4–/– but not IL‐4+/+ mice resulted in significant reductions in splenocyte IFN‐γ mRNA transcripts and in serum IFN‐γ levels. These results demonstrate that IL‐4 has an important role in effective anti‐leishmanial chemotherapy which seems to be related to modulation of IFN‐γ production.

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Blockade of CTLA-4 Enhances Host Resistance to the Intracellular Pathogen,Leishmania donovani

Cited by 121 publications

References 56 publications

A molecular signature for IL-10–producing Th1 cells in protozoan parasitic diseases

A molecular signature for IL-10–producing Th1 cells in protozoan parasitic diseases

Rickettsia Vaccine Candidate pVAX1-OmpB24 Stimulates TCD4+INF-γ+ and TCD8+INF-γ+ Lymphocytes in Autologous Co-Culture of Human Cells

Endogenous IL-4 is necessary for effective drug therapy against visceral leishmaniasis

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